Stimulation of cholesterol biosynthesis in mitochondrial complex I-deficiency lowers reductive stress and improves motor function and survival in mice

Tom J.J. Schirris, Sergio Rossell, Ria de Haas, Sanne J.C.M. Frambach, Charlotte A. Hoogstraten, Herma Renkema, Julien D. Beyrath, Peter H.G.M. Willems, Martijn A. Huynen, Jan A.M. Smeitink, Frans G.M. Russel*, Richard A. Notebaart

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The majority of cellular energy is produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. Failure of the first OXPHOS enzyme complex, NADH:ubiquinone oxidoreductase or complex I (CI), is associated with multiple signs and symptoms presenting at variable ages of onset. There is no approved drug treatment yet to slow or reverse the progression of CI-deficient disorders. Here, we present a comprehensive human metabolic network model of genetically characterized CI-deficient patient-derived fibroblasts. Model calculations predicted that increased cholesterol production, export, and utilization can counterbalance the surplus of reducing equivalents in patient-derived fibroblasts, as these pathways consume considerable amounts of NAD(P)H. We show that fibrates attenuated increased NAD(P)H levels and improved CI-deficient fibroblast growth by stimulating the production of cholesterol via enhancement of its cellular efflux. In CI-deficient (Ndufs4−/−) mice, fibrate treatment resulted in prolonged survival and improved motor function, which was accompanied by an increased cholesterol efflux from peritoneal macrophages. Our results shine a new light on the use of compensatory biological pathways in mitochondrial dysfunction, which may lead to novel therapeutic interventions for mitochondrial diseases for which currently no cure exists.

Original languageEnglish
Article number166062
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1867
Issue number4
DOIs
Publication statusPublished - 1 Apr 2021

Keywords

  • Cholesterol biosynthesis
  • Complex I deficiency
  • Leigh syndrome
  • Metabolic network modeling
  • NAD(P)H
  • Ndufs4 mice

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